Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on methamphetamine, nicotine, heroin, delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, and the endogenous cannabinoid anandamide. In previous experiments, we demonstrated persistent intravenous self-administration behavior by squirrel monkeys for doses of THC comparable to those in marijuana smoke inhaled by human, but monkeys had a cocaine self-administration history before the start of the THC experiments. We have now shown persistent intravenous THC self-administration behavior in squirrel monkeys with no previous drug history, further suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse. Recent experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems using rodent self-administration models. Since THC is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of cannabinoids in non-human primates. In one experiment, we studied the effects of naltrexone, an opioid antagonist clinically used for the treatment of opiate abuse or alcoholism, on THC self-administration behavior of squirrel monkeys. Self-administration behavior under both fixed-ratio and second-order schedules of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone. In contrast, naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions. This suggests a facilitatory modulation of cannabinoid reinforcement by endogenous opioid activity that is unmasked by treatment with an opioid antagonist, but other mechanisms cannot be ruled out. Also, we and others have recently reported that the cannabinoid CB1 receptor antagonist SR141716A reduces, but does not completely block, the reinforcing effects of heroin using fixed-ratio and progressive-ratio schedules of intravenous heroin injection in rats, further suggesting that opioid-cannabinoid interactions can be bi-directional. In a subsequent study in rats, we investigated whether the subjective effects of THC could be blocked or reduced by administration of opioid antagonists and whether opioid agonists could mimic or potentiate THC's subjective effects. The opioid antagonist naloxone decreased the discriminative effects of a training dose of 3 mg/kg THC, significantly shifting the THC dose-response curve to the right. When the opioid agonist morphine was substituted for THC, it did not produce THC-like discriminative effects, but it potentiated the discriminative effects of THC, shifting the THC dose-response curve to the left. Using in-vivo microdialysis, we found that the dose of THC, which served as the training stimulus for the drug-discrimination study, significantly increased extracellular levels of the endopioid beta-endorphin in the Ventral Tegmental Area (VTA), the origin of the dopaminergic mesolimbic system and a major brain area involved in reinforcing effects of opioids. Finally, bilateral microinjections of beta-endorphin directly into the VTA potentiated the discriminative effects of a threshold dose of THC. Thus, the subjective effects of THC appear to be mediated, at least in part, by release of beta-endorphin and activation of opioid receptors in areas involved in opioid reward and reinforcement. In another series of studies, the role of different neurotransmitter systems in the reinforcing effects of methamphetamine is being evaluated in rats and squirrel monkeys. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 hours showed downregulation of dopamine D2 autoreceptors in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Since sigma-1 receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants, we have now examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. As in previous studies, two groups of rats served as yoked controls and passively received an injection of either methamphetamine or saline (not contingent on responding) each time a response-contingent injection of methamphetamine was actively self-administered by a third group of rats. After 5 weeks rats were withdrawn from methamphetamine for 24 hours. Subsequently brains were dissected and protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that had learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. These neuroadaptive changes in Sig-1R may be related to the downregulation of D2 autoreceptors we previously observed and may contribute to the reinforcing effects of methamphetamine, either by potentiating the physiological and subjective effects of methamphetamine directly or by facilitating development of learned associations between the physiological and subjective effects of methamphetamine injections, environmental stimuli predicting the availability of methamphetamine, and operant nose-poking responses leading to injections.